JP5244189B2 - System and method for producing a dry formulation - Google Patents

Description

  The present invention relates to a spray-drying (spray-drying) system and a spray-drying method adapted to produce a small amount of powder.

  In the early stages of drug development, a vast number of new chemical compounds can often be synthesized using pioneering chemistry with considerable effort and expense to provide raw materials for various preclinical trial programs. Many. It is easy to recognize that these newly synthesized materials may appear in both extremely limited quantities and forms that are difficult to process. Therefore, this type of drug substance candidate is required to be in a manageable form that is more adapted to the models already developed so that the initial necessary steps can be taken to study these properties. . Already in general, some general requirements may be set in this kind of methodology to improve its manageability. This methodology will preferably increase the dissolution rate of the compound in an aqueous system. This methodology will tolerate less process loss, and can preferably be used at ambient temperature, and will be in a very defined form for the compound.

  A system that provides inhalation exposure to outline both the suitability of drug candidates for delivery to the lung and to study clinical and toxic effects demonstrates a highly desirable preclinical model. ing. A suitable such exposure system using aerosolized drug candidates is described in Swedish patent application No. 0701569-6, while a target lung model is described in US patent application No. 60 / 934,070, Useful aerosolization devices are described in US Pat. No. 6,003,512. At the same time, this technology, later referred to as dust gun technology, provides a powerful tool in drug development that can process small quantities of powdery compounds, ie, milligram scale. Also, this technique, which allows for effective powder disintegration, still requires a substrate particle size that is smaller than or equal to the desired particle size distribution of the generated aerosol. There are several methods that can be used to provide the dust gun system with a fine powder sufficient to allow the generation of a respirable aerosol including milling, spray drying, and supercritical spray drying. Of these methods, conventional spray drying has the potential to allow very small batch production of powders with sufficiently high yields for use with very expensive drug candidates. In milling operations, there is too much loss in the conduit walls, and in the case of supercritical spray drying, relatively complex process adjustments consume too much material before obtaining sufficient quantities and quality of raw materials Tend.

  Even in the case of conventional spray drying systems such as commercial as well as custom made (Laedhe et al., 2006), production targets are usually on the scale of grams or more. This is too much to be optimal in the case of early synthesis steps in preclinical development. To be optimal for utilizing the dust gun system in early drug development, the appropriate amount of powder formulation in the spray drying system will be in the range of 20 mg to 100 mg. For such low production targets, one important advantage is reached compared to higher maximum capacity systems, i.e., the solvent vapor from the aerosol stream in the drying tower before separating the particles. Many can be removed. Most commercial systems with higher production targets rely on the use of heated dry gas to quickly evaporate the solvent from the particles before separating the particles from the process stream using a filter or cyclone. (Laedhe et al., 2006). However, in the case of a production target of about 100 mg, it is inappropriate if the volumetric flow rate through the device increases. Already at higher production targets, cyclone product yields are usually much lower than 60% (Prinn et al., 2002, and Maury et al., 2005). Solvent vapor removal prior to direct use of the resulting aerosol for inhalation exposure has been previously described (Pham and Wiedmann, 1999, and Wiedmann and Ravichandan, 2001). These systems utilize diffusion drying by passing the process aerosol through the tower using a vapor absorbing material accessible through the multi-hole walls of the drying tower. The disadvantages of this system are the cumbersome process in which the drying tower absorbent pellets must be replaced periodically, and the absorbent material is contaminated with the dried material. Countercurrent drying is typically used, for example, in the food industry producing powdered milk. However, in these examples, the product particles are dried by gravity settling in an ascending dry air stream (Piatkowski and Zbickinski, 2007). In that case, the sedimentation rate of the particles must be on the order of 10 cm / sec, which limits the production of particles larger than 50 μm. This countercurrent method cannot be used for drugs with desired product particles smaller than 5 μm, where the sedimentation rate is in the range of mm / min. Thus, suitable for drug candidates in the form of spray-drying systems and dry, nearly solvent-free powders, particularly powders having a particle size in the range of 1 μm to 5 μm, suitable for generating breathable aerosols with dust gun technology There is a need for a system that is adapted to obtain a small amount of a manageable formulation.

  As described in the next section, the present invention is suitable for aerosol generation, but is also useful for several other applications beyond the context of drug development, a natural, newly synthesized It is an object of the present invention to provide a dry solvent-free powder from a small amount of the chemical compound formed.

US Pat. No. 6,003,512

Bird RB, Stewart WE and Lightfoot EN (1960), “Transport Phenomena”, Transport Phenomena. John Wiley & Sons, New York. Ewing P, EirefeltS, Andersson P, Blomgren A, Ryrfeldt A and Gerde P (2008), "Short inhalation exposures of the isolated and perfused rat lung" the detailed pharmacokinetics of budesonide, formoterol and terbutaline. JAerosol Med 21: 1-12. Ladhe A, Raula J, Kauppinen EI, Watanabe W, Ahonen PP and Brown DP (2006), `` Aerosol synthesis of inhalation particles via a droplet-to-particle '' method. Particle Science and Technology 24: 71-84. Maury M, Murphy K, Kumar S5 Shi L and Lee G (2005), "Effects of process variables on the powder yield of spray- dried trehalose on a laboratory spray-dryer. Eur JPharm Biopharm 59: 565-573. Mirme A, Tamm E, Mordas G, Vana M, Uin J, Mirme S, Bernotas T, Laakso L, Hirsikko A and Kulmala M (2007), `` A wide-range multichannel air ion spectrometer '' A wide-range multi channel air ion spectrometer. Boreal Environment Research 12: 247-264. Pham S and Wiedmann TS (1999), “Analysis of a diffusion dryer for the respiratory delivery of poorly water soluble drugs. Pharm Res 16: 1857-1863. Piatkowski M and Zbicinski I (2007), “Analysis of the mechanism of counter-current spray drying. Transport in Porous Media 66: 1573-1634. Prinn KB, Costantino HR and Tracy M (2002), “Statistical modeling of protein spray drying at the lab scale.” AAPS PharmSciTech 3: E4. Rubow KL, Marple VA, Olin J and McCawley MA (1987), "Personal cascade impactor: design, evaluation and calibration" A personal cascade impactor: design, evaluation and calibration. Am IndHyg Assoc J 48: 532-538 . Wiedmann TS and Ravichandran A (2001), “Ultrasonic nebulization system for respiratory drug delivery.” Pharm Dev Technol 6: 83-89.

  The object of the present invention is to provide a spray-drying system adapted for reliable performance which obtains a small amount of powder formulation with negligible loss.

  It is also an object of the present invention to provide a spray drying system that overcomes settling velocity limitations associated with conventional countercurrent systems.

  Another object of the present invention is to provide a spray-drying system that allows for a suitably extended residence time at ambient temperature, thereby treating agents that are normally susceptible to chemical changes.

  These and other objects will be apparent from the following specification and the appended claims.

  In general, the present invention relates to a spray drying system adapted to provide a composition of dried or essentially solvent-free particles from a solution of a drug. The process flow described in this system and method is commonly referred to as a “gas flow” or “air flow”, and these terms are used interchangeably to describe the present invention and in this context. Within the scope of the above, it is intended to mean a medium that forms a flowing gas capable of transporting vaporized solvent that does not impair or alter the properties of the agent processed by the system. Those skilled in the art will readily understand that selectively dehumidified ambient air is a useful transport medium, for example, when a special protective environment is required for certain drugs. It will also be appreciated that various other media can be used, such as, but not limited to, inert gases, gases such as nitrogen and argon, to exchange or supplement air in certain environments. In general, it is expected that this type of gas can be processed and transported by the invented system and method in a manner similar to that described for ambient air. In a similar manner, the system according to the invention can be operated at temperatures away from ambient temperature, for example using an inert gas at an excessively elevated temperature above room temperature.

The system generally comprises a vertical tubular reactor (tube reactor), which reacts with solvent from a process stream supplied with aerosol droplets of solution descending from its top against a rising air stream. It is configured to allow countercurrent removal. The tubular reactor comprises a porous process tube for transfer of the process stream from the outlet of the spray generating device capable of generating the aerosol droplets of the solution to the dry particle collection device. Further, the tubular reactor comprises a membrane sleeve that essentially surrounds the surrounding region of the process tube and separates the descending process stream (down process stream ) from the ascending air stream (up stream gas stream) . The membrane sleeve is permeable to allow diffusion of the vaporized solvent from the process stream to the ascending air stream, but prevents convective mixing of the ascending and descending flows. The membrane sleeve is advantageously a thin sheet that allows the diffusion of the vaporized solvent with a controlled solvent absorption capacity of the solvent.
The solvent will then be temporarily absorbed into the membrane by adsorption or absorption while obtaining an equilibrium between sorption and desorption. Thereby, the diffusion capacity from the process stream to the rising air stream is increased. The membrane sleeve can be treated with a drug to modify its absorption capacity to accommodate different solvents with different polarities and other chemical properties. In one example, the membrane sleeve can be a thin paper sheet. The paper sheet to obtain proper diffusivity and controlled adsorption is made from rice paper having a specific weight of about 14 grams per square meter, at least when the paper is a solvent.

  The tubular reactor also comprises a reactor housing that covers the process tube and membrane sleeve, preferably in a sealed manner. The housing is provided with features for introducing the required process fluid and driving the reactor. The aerosol generating device is directed downwards into a process tube provided at the top of the reactor and comprising a liquid chamber for containing a quantity of solvent having a drug to be processed on the particles, i.e. an aerosol It has an opening located at its bottom so that a droplet can be dispensed. The nebulizer is preferably a mesh nebulizer that does not require any feed gas (unlike a jet nebulizer). It may also be preferable to use a vacuum in the liquid chamber, especially when a solution with a small surface tension is used, or when leaching of a liquid with large dripping droplets that prevents aerosolization is expected. is there. A vacuum of about 2 cmvp to 10 cmvp is usually sufficient to shrink the liquid, allowing very short drive cycles. A dynamic vacuum with a pressurized air injector is a practical method. These configurations increase the flexibility of aerosolization solutions that can be implemented for use in the present invention to extend to fat-soluble materials, while at the same time allowing for excellent control throughout the aerosolization process. Usually, aerosol droplets in the size range of 4 μm to 20 μm are formed. In this regard, skilled artisans recognize that the droplet size depends on the physical and chemical properties of the solution.

  The system is provided with means for supplying inlet air from the air drying tower to the tubular reactor. This inlet air flow measuring device is located between the process tube and the air drying tower. The flow measurement device is a precision control device such as a high-resolution respiratory flow meter because it is sufficiently sensitive to the aerosol aerosol dispense pulse from the nebulizer near the air flow inlet to the process tube . Consequently, this function serves as a surveying control instrument for the drying process, for example by indicating when the nebulizer is empty.

  In addition, the system comprises a device for introducing inlet air into the perforated process tube, which device preferably provides a laminar process flow containing descending aerosol droplets. The device is generally circular in cross section, thereby enclosing the nebulizer opening and generating a process flow so that aerosol droplets can be transported and directed toward the radial center of the process tube. A plurality of outlet orifices are provided that are disposed along the peripheral region of the device. The inlet orifice is preferably bent and arranged at an angle with respect to the outlet channel having a principal axis offset relative to the cross-sectional radius of the inlet air device. That is, the longitudinal extension of the orifice channel forms an acute angle with the normal to the surface of the inlet device. In addition, the inlet air device preferably has a plurality of orifices evenly distributed around the central portion of its surrounding area to create a tangential flow in the process tube to generate the process flow.

  The descending process stream that transports the dry aerosol is preferably generated by a vacuum source connected to the bottom of the process tube. The descending process flow is laminar and the ascending air stream for removing the vaporized solvent from the tubular reactor is preferably laminar with a higher flow rate than the descending process stream. The ascending air flow is adapted to perform a swirling motion around the membrane sleeve. For this purpose, the tubular reactor has a tangential mouthpiece for generating an upward air flow, and in order to sustain the swirl upward flow, the tubular reactor is for the upward air flow. With tangential outlets.

  In a special embodiment for reducing membrane wall aerosol loss, the ascending air flow is configured to generate a radial inflow of air (sheath air) through the membrane. Preferably, the radial sheath air inflow rate is less than the diffusivity of vapor through the membrane, i.e., the Peclet number in the membrane is substantially less than one.

The system is provided with a sealed loop configuration for recirculating an ascending gas stream containing a large amount of ascending solvent and for purifying the stream with solvent in a column capable of absorbing the solvent. It is preferable that it can be transferred for introduction into the vessel. This configuration includes means connected to a tubular reactor and transported through a desolvation tower well known in the art, while the solvent absorbing material is easy to solvent properties and other process conditions. Can adapt to. In general, this loop configuration can include a drive fan, preferably a mass flow sensor. In order to establish an ascending air flow that permits radial sheath air flow, an air injector is provided for introducing a dry air flow, whereby the ascending air is at least from an equal flow rate to a descending process flow rate. It is arranged to make the above-described spiral convection air stream having a flow rate up to 50 times greater. In general, it is preferred that the upflow has a higher flow rate than the downflow. The injected air preferably merges with the recycle stream before entering the tubular reactor.

  The ability of the system to be configured to reduce the loss of aerosolized material on the membrane wall is an important aspect of the system according to the present invention. For this purpose, an electrostatic charge neutralizing device such as Po-210-source is placed near the nebulizer opening. Many other types of neutralization devices are contemplated by those skilled in the art. Also, other means for reducing or eliminating material loss have been discussed previously and can be used separately or in combination when practicing the present invention. The previously described process tube inlet air configuration, radial sheath air flow, and laminar flow conditions inside the process tube contribute to increased yield.

According to another aspect, the present invention is a method of preparing a composition of dry or essentially solvent-free particles from a solution of a drug, wherein the drug solution is supplied to a device for generating an aerosol Generating a descending process flow in the form of an aerosolized droplet air stream having a low flow rate in the perforated process tube; and an ascending air stream to allow countercurrent removal of solvent from the process stream. Generating the ascending flow with a substantially higher flow rate than the descending flow, and providing a membrane to separate the process stream and the ascending air flow through the process stream for aerosol drying. allowing the diffusion transfer of the solvent vaporized to the upward flow from the steps of providing a film, finally, the particle dried from the process stream Before removing relates to a method of a process flow for a time sufficient to remove substantially all of the solvent vapor and a step that can be lowered within the process tube. This aerosolization device can be outlined as previously discussed, vacuum can be added, and the descending and rising flows are arranged to be laminar. For the reasons discussed above, the step of carefully monitoring the flow rate of the process tube inlet air and thereby obtaining process control is preferred. Also preferably and as discussed above, the method includes the steps of sealingly transporting a high solvent-enriched air stream leaving the membrane toward the solvent absorption tower and through the tower for desolvation. A recirculation step comprising transferring an air flow and recontacting the air flow with the membrane for ascending through the reactor. The method preferably includes introducing an ascending air stream into the tubular reactor in a tangential direction to generate a swirl flow around the membrane. Furthermore, the swirl motion can be sustained by taking the rising air flow from the tubular reactor in a tangential direction. According to a special embodiment suitable for counteracting the loss of aerosolized material to the membrane, a controlled stream of dry air is introduced into the desorbed air stream to the desorbed air stream, thereby This air flow is arranged to allow radial sheath air flow through the opposite membrane for diffusive transport. In order to centrally stabilize the aerosol dispensed from the process tube nebulizer, a previously rotating air inlet device generates a gently rotating inlet air stream. According to another embodiment, the method further comprises detecting or monitoring the performance of the aerosol generating device by carefully measuring the inlet air flow to the process tube. Advantageously, if the process tube air flow through the dry particle collection device is constant, the evaporation of each aerosol pulse will result in a small increase in the recorded air flow in a short time. Thereby, the performance of the aerosol generating device can be monitored including the emptying of its liquid container. Further, the method includes detecting the flow rate of the stream after desorption of the solvent after the absorption tower, and detecting the concentration of the high solvent content stream before entering the absorption tower. Monitoring the mass flux of the solvent can be included. The solvent concentration is also measured in the gas stream that penetrates the particle collection device.

  In the case of the system and method according to the invention, the limited settling rate for countercurrent drying is avoided by using complete flow separation between the aerosol-carrying product stream and the drying stream. The two countercurrent streams are separated by a vapor permeation barrier or membrane. This membrane or barrier prevents conventional mixing between each gas stream, but allows diffusion equilibrium of solvent vapor from high to low concentrations. Typically, the residence time in the process tube is in the range of 1 minute, which is much longer than most existing systems with residence times on the order of 1 second. The countercurrent drying stream has a residence time that is 1/10 to approximately equal to the residence time of the aerosol stream.

  As explained, this system and method is useful for providing dry particle formulations for some drugs that are dissolved in a suitable solvent. The medicament may comprise or consist of a pharmaceutically active compound or mixture of compounds at the time of use.

  The invention will now be described in more detail by way of exemplary embodiments and with reference to the accompanying drawings. However, the embodiments described and illustrated are not to be construed as limiting the scope of the invention as described by the appended claims.

It is the schematic which shows the spray-drying system by embodiment. It is the schematic which shows the longitudinal cross-sectional view of a tubular reactor. FIG. 2 is a schematic view showing a part of a process air inlet by a cross-sectional view. It is the schematic which shows the outer periphery of an air inlet device. It is a figure which shows the measured value of the water vapor | steam of the spray-drying system at the time of an action | operation. It is a figure which shows the measured value of the water vapor | steam of the spray-drying system at the time of an action | operation. FIG. 4 shows the particle size distribution of lactase after the system is operated with a lactase solution. FIG. 4 shows the particle size distribution of lactase after the system is operated with a lactase solution.

  Next, the present invention will be described with reference to FIG. The spray drying system comprises a generally vertical tubular reactor (tube reactor) 101 where the dissolved drug aerosol is dried. There are two streams through the tubular reactor 101, the first being a descending process stream of gas fed with aerosol droplets. The second stream is a countercurrent rising air stream that is fed to the bottom of the tubular reactor 101 and absorbs solvent from the process stream. A solvent absorption tower 102 is connected to the tubular reactor 101, and a recirculation fan 103 supplies dry air to the tubular reactor 101 and recirculates it through the solvent absorption tower 102. The system also includes a filter holder 104 where the filter 105 collects dried particles. The process flow is fed from the air drying tower 106 to the top of the tubular reactor 101 via a measuring device consisting of a Fleisch intake flow meter 107 monitored by a pressure transducer 108. The liquid chamber of the mesh nebulizer 109 (Aeroneb Lab Type) is filled with the solution to be dried. A vacuum apparatus is connected to the filter holder 104 at the bottom of the tubular reactor 101 and pumps the process stream from the tubular reactor 101 through this filter. The vacuuming device includes a vacuum pump 110, a rotameter, and a vacuum gauge 114. The mass flow sensor 111 is a hot wire anemometer, which detects the flow from the absorption tower 102 and detects the humidity of the dry air. The liquid chamber (not shown) of the nebulizer is evacuated by connecting the vacuum ejector 112 to the vacuum lid 113. The air injector 115 is adapted to inject some extra dry air into the system.

  With reference to FIG. 2, the spray drying process in a tubular reactor 201 (previously called 101) is illustrated. Tubular reactor 201 includes a perforated process tube 202 and a membrane sleeve 203. A descending process stream 204 of gas is fed into the process tube 202 along with aerosol droplets 205 from a nebulizer 209 (previously referred to as 109). An upward flow 206 of dry air from the recirculation fan 103 (shown in FIG. 1) flows spirally along the membrane sleeve 203. Continuously, solvent vapor from the aerosolized droplets 205 passes through the perforated process tube 202, diffuses through the membrane sleeve 203, and is transported by the rising air flow 206 of dry air. Further, additional controlled inflow of dry air from the air injector 115 (shown in FIG. 1) causes inflow of radial sheath air 207 through the membrane sleeve 203. This inflow prevents aerosolized particles from settling on the membrane sleeve and reduces particle loss.

  3a and 3b, an inlet air inlet device 301 is described. An inlet device 301 surrounds the opening of the nebulizer 109 and supplies inlet air through a number of holes 302 distributed equidistantly on the surface. The longitudinal extension of each hole has an acute angle α 303 with respect to this normal, unlike the normal of the surface of the inlet device 301 so as to create a vortex flow of the inlet air.

This system is intended to dry powder dosages of 10 mg to 500 mg and the size of the particles is in the range of 1 μm to 5 μm. The degree of material yield is greater than 80%. The size of the aerosol droplet 205 to be dried is in the range between 4 μm and 20 μm. In this embodiment, the length of the tubular reactor 101 is 900 mm and the diameter of the porous process tube 202 is 50 mm. The process tube is surrounded by a membrane sleeve made from rice paper having a specific weight of 14 g / m ² . The air inlet device 301 is formed like a cylinder having an outer shape of 50 mm, a height of 14 mm, and a material thickness of 1.2 mm. Forty holes distributed equidistantly through the material are made with a diameter of 1.5 mm on the surface and 7 mm from the outer circumference. In order to create a gently rotating flow in the area of the nebulizer outlet, the angle between the longitudinal extension of the hole 302 through the outer periphery of the air inlet device and the normal or radius of the device is 20 °. The air descending process flow 204 is 1 liter / min, the dry air ascending flow 206 is 30 liter / min to 50 liter / min, and the sheath air additional flow 207 is less than 1 liter / min. Is also small. The flow of dry air and sheath air is a continuous flow that is precisely controlled. A vacuum of 2 cmvp to 10 cmvp is supplied to the top of the nebulizer liquid chamber. The volume of the absorption tower is 4 liters. The aerosol is generated in an Aeroneb Lab mesh nebulizer 209 that operates at 4% of its total power. An aerosol with 75% relative humidity can be dried with this system, so the relative humidity at the filter is between 5% and 10%. The process flow measurement device can record down to 0.1 μL. The inflow rate of the sheath air is much smaller than the diffusivity through the membrane, that is, the Peclet number in the membrane is substantially less than one. After passing through the drying tower, the powder is collected by all filters. The filter cake is gently scraped off the filter with a rubber blade. The residual powder of the filter can be dissolved in the desired solvent for further use. If the vapor concentration in the drying tower is low, the probability of an explosion will be very small, and if the evaporation rate of a liquid that shows a small amount of vapor in the tower at any given time is low, any accidental It will make harmless explosions harmless. At most, there can be 20 mg of vapor in the tower at any single point. Therefore, it may not be necessary to use an inert gas in the drying process in terms of accidental danger.

  Reference is now made to FIG. 4a for illustrating the operation of a spray drying system according to the present invention by way of example. This figure shows the measured steam as relative humidity during the start of the Aeroneb nebulizer at 4% drive cycle (20 ms on, 480 ms off). The absorption tower flow rate was 50 L / min during the first part of the test, but was reduced to 15 L / min after 800 seconds. Humidity increased as expected as it was diluted to a smaller amount of air. The mass balance for the drying tower and later demonstrated by humidity measurements is that more than 90% of the water entering the drying tower with the atomized solution is removed before the particles reach the bottom filter. Indicates. FIG. 4b shows the drying out of the drying tower after turning off the nebulizer. The flow rate of the absorption tower is 15 L / min.

  FIGS. 5a and 5b show examples of lactase powder dissolved and re-dried with a spray drying system illustrated as a 10% solution in water. The Aeroneb nebulizer operated at 4% of its full power. Both powder samples were aerosolized with a dust gun aerosol generator (Ewing et al., 2008) and had a particle size distribution characterized by the Marple Cascade Impactor (Rubow et al., 1987). FIG. 5a shows that ground lactase (obtained from AstraZeneca) has an average particle size (MMAD) of 7.0 micrometers, and the spray-dried lactase of the exemplary system according to the invention has an average of 4.7 micrometers. With particles (MMAD) (FIG. 5b). The yield of a 100 mg 10 mg solution of lactase was 75%.

Reducing the aerosol loss of the film-coated walls of the aerosol part of the drying tower is accomplished in four ways. That is, it is as follows.
1) Neutralize the electrostatic charge of the newly generated aerosol with a Po-210 source at the nebulizer end of the tower.
2) A laminar flow configuration is used in the tower. The Reynolds number inside the tower is about 30, which is well below the beginning of the turbulent transition region at 2100. The flow form of the annular dry air flow is also well in the laminar flow region.
3) To stabilize the flow around the aerosol puffs while dissipating the kinetic energy from the nebulizer and keep them in the center of the tower, the carrier gas in the nebulizer is passed around the mouthpiece of the nebulizer Rotate gently inside.
4) Use the new radial sheath air method in the rest of the tower.

To obtain radial sheath air flow and reduce system loss, a controlled dry air stream is added to the system's external dry air circulation just prior to the bottom inlet of the drying tower. Here we discuss some design considerations. To reduce aerosol wall loss, years have been spent injecting clean air axially in the form of an annulus surrounding the aerosol stream at the inlet end of the tubular tower (Mirme et al., 2007). ). Since the dry air circulation is completely closed to the ambient air, a controlled inflow of sheath air through the membrane and into the aerosol portion can be achieved. The intention is to use the membrane as a diffuser for the sheath air flow so that the incoming sheath air is evenly distributed above the inside of the membrane-coated tube. By doing so, it is possible to further reduce the wall loss of the aerosol before being deposited on the filter. The radial inflow velocity of sheath air is much slower than the radial outflow of steam due to molecular diffusion, a relationship that can be characterized by the so-called Peclet number (Bird et al., 1960). The Peclet number (Pe) is the ratio between movement by convection and movement by diffusion of a substance in a flowing gas or liquid, ie Pe = L * V / D, where L is Characteristic length (m), V is a flow velocity (m / s), and D is a molecular diffusivity (m ² / s) of vapor molecules. In current systems, the characteristic length is the wall thickness of the perforated tube or 1 mm. The flow rate is the sheath air flow rate through the tube wall divided by the total porous hole area. The normal diffusivity of air vapor molecules at 20 ° C. is about 1 × 10 ⁻⁵ (m ² / s). At a sheath air flow rate of 0.3 L / min, the Pe number at the membrane is about 0.01, much less than one. When the Pe number is less than 1, the movement by diffusion dominates the movement by convection, and thus the diffusion from the membrane is much faster than this movement of air into the membrane for sheath air. However, using the same definition for the diffusion of dry particles, Pe >> 1 is given, indicating that this air movement instead dominates the diffusion of the particles and thus pushes the particles away from the tube wall. In the case of 1 μm particles, the air diffusivity is about 3 × 10 ⁻¹¹ (m ² / s). For this type of particle, the Peclet number at the membrane is about 2000, which is in a smaller range for normal dry aerosols.

  The described system has three advantages. That is, it is as follows. I) The separated powder product is easier to process if it contains only a small amount of residual solvent. II) This system relies on residence time in the drying tower in minutes instead of residence time in seconds as in most current designs. Longer residence times allow the particles to dry at room temperature. Thus, heat labile materials such as proteins and peptides can be dried using standard methods. III) In the case of countercurrent drying, a separation column can be used for the vapor-absorbing material, ie activated carbon or drierite. This absorbent material is not contaminated by direct contact with the spray product and can therefore be easily regenerated.

101,210 tubular reactor; 115 air injector;
202 perforated process tube; 203 membrane sleeve; 204 process flow;
109,209 nebulizer; 205 aerosol droplets;
206 Upflow of dry air; 207 Radial sheath air.

Claims (15)

A spray drying system configured to provide a composition of dried or essentially solvent-free particles from a drug solution, comprising a vertical tubular reactor, the tubular reactor comprising an ascending gas flow Against the descending process stream with aerosol droplets of solution descending from the top of the reactor, the reactor comprising:
(I) a porous process tube for transferring the descending process stream from an outlet of an aerosol generating device capable of generating the aerosol droplets of solution to a dry particle collection device;
(Ii) said surrounding the peripheral region of the porous process tube, while permitting the diffusion of the solvent vaporized to the ascending gas flow from the descending process stream, film sleeve separating the descending process stream from the ascending gas stream,
(Iii) A system comprising: the porous process tube provided with means for introducing and / or removing the descending process stream and a reactor housing hermetically covering the membrane sleeve. The aerosol generating device located at the top of the tubular reactor is a downward-acting mesh nebulizer having an opening at the bottom so that aerosol droplets can be dispensed into the porous process tube. The system according to claim 1. 3. The system of claim 2 , wherein the mesh nebulizer liquid chamber that receives the solution of drug is coupled to means for establishing a pressure below the ambient pressure of the chamber.   4. A system according to claim 2 or 3, wherein the aerosol droplets are in the size range of 4 [mu] m to 20 [mu] m. The membrane sleeve is a thin sheet that allows diffusion of the solvent from the descending process stream to the ascending gas stream and has a controlled solvent absorption capacity , the sheet having a ratio of about 14 grams per square meter. The system according to claim 1, wherein the system is a paper sheet having a weight. Means for supplying a flowing gas to the tube reactor is provided from the gas drying tower, said means Tei Rukoto an inlet flow measuring device is disposed between the perforated process tube and the gas drying tower The system according to claim 1, wherein:   7. The system of claim 6, wherein the system comprises a device for introducing an incoming gas into the perforated process tube adapted to supply a laminar process flow comprising descending aerosol droplets. . The device is generally annular in cross-section, thereby enclosing the nebulizer opening and generating a process flow so that the aerosol droplets can be transported and directed toward the radial center of the porous process tube The system of claim 7, wherein a plurality of outlet orifices are provided along a peripheral region of the device.   9. The system of claim 8, wherein the orifice is bent and arranged at an angle with an outlet channel having a principal axis offset relative to a cross-sectional radius of the device introducing the inflow gas. 10. A system according to any preceding claim, wherein the process flow is generated by a vacuum source connected to the bottom of the perforated process tube. A method of preparing a composition of dry particles essentially free of solvent from a solution of a drug comprising the steps of:
(I) supplying a drug solution to a device for generating an aerosol; (ii) a descending descending process flow in the form of an aerosolized droplet gas stream having a low flow rate in a porous process tube; A step of generating
The ascending gas flow as (iii) from the descending process stream can countercurrent removal of the solvent, substantially greater rate than the descending process stream, comprising the steps of generating,
(Iv) providing a membrane to separate the descending process stream and the ascending gas stream and permit diffusive transfer of vaporized solvent from the descending process stream to the ascending gas stream to dry the aerosol therethrough; Providing a membrane; and
(V) prior to removing the dried particles from the descending process stream, said process stream for a time sufficient to remove substantially all of the solvent vapor and a step that can be lowered in the perforated process tube A method characterized by comprising. The method of claim 11, wherein the ascending gas flow and the descending process stream descends are both laminar. Comprising the steps of sealingly transferring ascending gas stream comprising most of the solvent through the membrane towards the solvent absorption tower,
Transferring the gas stream through the solvent absorber for desolvation;
The method of claim 11, comprising recontacting the gas stream with the membrane to ascend through the reactor without generating a radial flow of gas through the membrane. Comprising the steps of sealingly transferring ascending gas stream comprising the number of solvent through the membrane towards the solvent absorption tower,
Transferring the gas stream through the solvent absorber for desolvation;
Re-contacting the gas stream with the membrane to ascend through the reactor, and at the same time, a dry gas flow into the gas stream desorbed to produce a corresponding radial inflow of sheath gas through the membrane. 12. The method of claim 11, comprising introducing a controlled flow.   15. The method of claim 14, wherein the ascending gas flow is arranged to allow radial sheath flow through the membrane in the opposite direction of the diffusive transport.

Images